Canadian Adverse Drug Reaction Newsletter
Volume 7 · Number 2 · April 1997
In This Issue
Adverse drug reaction
reporting -- 1996
Potential abuse of butorphanol nasal spray
Aminoglycoside ear drops and ototoxicity
Adverse drug reaction reporting --
1996
More than 4000 spontaneous case reports in Canada were submitted
to the Canadian Adverse Drug Reaction Monitoring Program (CADRMP) in 1996. These
reports were received from a variety of sources (Fig. 1). Most of the reports
were from drug manufacturers, which are under regulatory obligation to systematically
forward certain reports that come to their attention. A significant number of
the reports also came from the 4 regional ADR centres affiliated with the CADRMP.
Two of their objectives are to increase awareness and participation in ADR reporting
in their respective regions. Other important sources of reports were hospitals,
many of which have programs in place for identifying and reporting ADRs, and
physicians, pharmacists and others who reported directly to the CADRMP.
In most cases, the people who initiate the reports are health
professionals (physicians, pharmacists, nurses, dentists, coroners and others)
who suspect that a drug has played a role in the adverse reaction and
who voluntarily complete an ADR reporting form and forward it directly to the
CADRMP or indirectly through one of the other sources. The CADRMP would like
to thank all of you for your important contribution to monitoring the safety
of drugs in Canada and to encourage you to continue your efforts.
This article is under the responsibility of: Claire-Marie Wray,
PhD, Bureau of Drug Surveillance
Fig. 1: Source of reports of adverse drug reactions (ADRs)
in Canada in 1996. Mnfr = drug manufacturers, RC = regional ADR centres, Hosp
= hospitals, Comm = pharmacists and physicians in the community, and Other =
professional associations, nursing homes, Health Protection Branch regional
inspectors, coroners, nurses, dentists and others.
Potential abuse of butorphanol nasal spray
Since November 1994 the CADRMP has received 48 reports of ADRs
associated with the administration of butorphanol tartrate nasal spray (Stadol NSTM).
The CADRMP reviewed 15 reports that indicated suspected drug-seeking behaviour,
drug abuse or addiction.
The age of the patients (9 women, 3 men, 3 sex not specified)
ranged from 22 to 51 years (age was unknown in 6 cases). The reasons for use
were stated as migraine and migraine headache (8 cases), headache (2 cases),
and cluster headaches and intractable migraine (1 case); a reason was not documented
in 4 cases.
Information on the total number of bottles used, the duration
of therapy and any other significant comments in the reports is provided in
Table 1. Significant findings from these reports include
the receipt by 1 patient of 257 bottles of the nasal spray over 9 months and
the receipt by 4 patients of prescriptions from 2 or more practitioners. One
of the 4 patients received prescriptions from 34 practitioners and had them
filled at 23 different pharmacies. In addition, 4 patients had been or were
currently using opioid medications such as drugs containing codeine or oxycodone
or meperidine, 2 had a history of opioid abuse, and 1 had a history of alcohol
abuse.
In addition to these 15 abuse-related ADR reports, the Bureau
of Drug Surveillance received 41 Psychoactive Drug Loss/Theft/Forgery reports
indicating that, from February 1995 to May 1996, 2 units of butorphanol nasal
spray were lost, 11 were obtained by forged prescriptions, and 53 were stolen
(48 by break and entry on different occasions and 5 by armed robbery).
Furthermore, in January 1997 butorphanol nasal spray was added
to one province's Prescription Practice Program. This program monitors prescriptions
filled by pharmacists to screen for such anomalies as abuse, multiple prescribers
and prescription forgeries.
Although butorphanol nasal spray may have a lower abuse potential
than morphine, reports suggestive of possible abuse are mentioned in the precautions
section of the current product monograph. The section also states that special
care should be exercised in administering butorphanol to emotionally unstable
patients and to patients with a history of drug misuse.
The CADRMP would like to remind health practitioners of its
interest in receiving any report on abuse-related reactions. This information
contributes to the determination of the relative potential for abuse of any
drug. Furthermore, drug abuse or dependence is considered a serious ADR because
it can be life-threatening or may result in persistent or significant disability.
Additional information on butorphanol nasal spray
Butorphanol nasal spray (Stadol NSTM) is a
controlled drug under Schedule G of the Food and Drugs Act and was approved
for marketing in Canada in July 1994. It is indicated for the relief of moderate
to severe acute pain. As stated in the product monograph, butorphanol acts as
an agonist at kappa-opioid receptors and a mixed agonist-antagonist at mu-opioid
receptors in the central nervous system to alter the perception of pain. Although,
as a class, the mixed agonist-antagonist opioid analgesics have a much lower
abuse potential than morphine, all such drugs have been reported to be abused.
The analgesic potency of butorphanol is about 4 to 8 times
that of morphine, 30 to 40 times that of meperidine and 16 to 24 times that
of pentazocine.1 The onset of action and the systemic
bioavailability of butorphanol administered intranasally are similar to those
achieved following parenteral administration.
Table 1: Details of 15 abuse-related adverse
reactions to butorphanol nasal spray
| Case |
Age/sex |
Duration
of therapy |
No. of bottles used* |
Additional comments in report |
| 1 |
30/F |
20 d |
23 |
Patient complained that 1 bottle contained water |
| 2 |
44/F |
4 mo |
83 |
Prescriptions from 2 doctors; dependence problems |
| 3 |
22/F |
4½ mo |
24 |
Prescriptions from several doctors; renewed every
few days |
| 4 |
NS+/F |
6 mo |
105 |
Prescriptions from 34 doctors; filled at 23 pharmacies |
| 5 |
NS/M |
7 mo |
80 |
Concomitant use of drugs containing codeine or oxycodone;
patient requested replacement of 6 bottles, negotiated the number of refills
and reported problems with the seal and pump mechanism |
| 6 |
42/F |
8 mo |
NS; use listed as "out of control" |
History of similar use of drugs containing codeine;
patient admitted to hospital for 11 d for withdrawal |
| 7 |
30/F |
9 mo |
257 |
|
| 8 |
51/M |
l yr |
1 every 1-2 wk |
Concomitant use of drugs containing codeine; patient
claimed lack of effect of butorphanol; patient requested replacement of
2 bottles |
| 9 |
NS/NS |
>1 yr |
> 2 per wk |
| 10 |
NS/M |
NS |
115 |
| 11 |
33/F |
NS |
Peak use: 1 bottle or 10 doses daily |
Use escalated quickly |
| 12 |
Late 40s/F |
NS |
NS; drug used every day |
Patient claimed that bottle was underfilled; physician
doubts authenticity of patient's claim and believes that patient abuses
butorphanol |
| 13 |
28/F |
NS |
NS |
Patient claimed that bottle had been diluted and requested
replacement; name is on a pharmacists' network alert list of narcotic abusers;
history of use of meperidine and a drug containing codeine |
| 14 |
NS/NS |
NS |
2 per wk |
Primary drug of abuse was an opioid |
| 15 |
NS/NS |
NS |
3 per wk |
Prescriptions from different doctors; history of alcohol
abuse |
*One 2.5 mL bottle provides 14-l5 intranasal
doses of l mg each.
†NS = not stated.
This article is under the responsibility of: Pascale Springuel,
BPharm, Bureau of Drug Surveillance
Reference
1.Gillis JC, Benfield P, Goa KL. Transnasal butorphanol: a review
of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential
in acute pain management. Drugs 1995;50:157-75.
Aminoglycoside ear drops and ototoxicity
Ototoxic effects are well-documented, clinically important
side effects of parenteral aminoglycoside use.1
However, not as well documented are ototoxic effects from topical aminoglycoside
use.2 Although aminoglycoside ear drops are generally
considered safe when used in the presence of an intact tympanic membrane, controversy
exists in the literature as to their safety in the presence of a
membrane defect.2-4
Ear drops may pass into the middle ear through a perforation
in the tympanic membrane and reach the inner ear through the round window membrane.
The resulting ototoxicity is in the form of cochlear damage (tinnitus and hearing
loss) or vestibular damage (vertigo and loss of balance), or both. The onset
is variable. Ototoxicity may appear rapidly with short-term exposure, slowly
during administration or some time after therapy has stopped. It begins with
tinnitus (most often a high-pitched ringing) and progresses to high-tone sensorineural
hearing loss and vestibular dysfunction, which may only be detected by special
tests (audiography, speech tests and electronystagmography with air caloric).
Because of the insidious nature of these effects and the minimal symptoms, significant
functional hearing and vestibular loss may occur before ototoxicity is detected.
The CADRMP has received 7 reports in which the use of GarasoneTM
ear drops (gentamicin sulfate and betamethasone sodium phosphate) in the presence
of tympanic-membrane perforation resulted in ototoxicity. A summary of the cases
follows:
The average age of the patients was 50 (range 32-66) years; 4 were women
and 3 were men.
Tympanic-membrane defects were due to an accidental perforation (1 case),
chronic ear problems (4), and bilateral myringotomy and tube insertion (2).
All patients were prescribed GarasoneTM drops to treat middle-ear
disorders with or without otorrhea. Some were also prescribed oral antibiotic
therapy (those specified were cefaclor, cefixime, ciprofloxacin and amoxicillin-clavulanate).
The ear drops were used for 10 days to 4 months, and in 1 case of chronic
ear discharge they were used intermittently for 2 years.
Complaints were of imbalance, vertigo, ataxia, oscillopsia (visual blurring
with head movement), tinnitus and hearing loss.
Subsequent investigations (vestibular testing and audiometry) confirmed
the absence or reduction of vestibular function as well as high-frequency
sensorineural hearing loss in all cases (bilateral in 5 cases, unilateral
in 2).
All patients were severely affected by the ototoxicity and some were incapacitated.
The drops were stopped. At the time of reporting, there was no improvement
in their symptoms. No other identifiable causes have been found that would
explain their status.
In all the cases the reporter felt that the adverse events were related
to the ear drops.
Although the CADRMP has not received reports of similar ADRs
for other aminoglycoside otic preparations, all aminoglycosides are capable
of affecting both cochlear and vestibular function.1
Some preferential toxicity is evident. Of the aminoglycosides commonly found
in ear drops (gentamicin, neomycin and framycetin) neomycin and framycetin primarily
affect auditory function, and gentamicin primarily affects vestibular function.
In the absence of hearing loss, the vestibular toxicity of gentamicin is often
missed or is assumed to be inadvertently due to labyrinthitis.4,5
Despite the widespread use of aminoglycoside ear drops, ototoxicity
in the presence of tympanic-membrane defects appears to occur in a small percentage
of patients.3,4 However, its incidence and prevalence
may be higher than reported because of the difficulty in distinguishing between
the natural course of the disease and the drug's toxicity. Because hearing loss
and vestibular paralysis are permanent in most cases, emphasis must be placed
on prevention. In most of the cases summarized in this article, hearing loss
occurred after prolonged use of the ear drops in the presence of tubes or tympanic-membrane
perforation. The following precautions in the treatment of ear infections in
such situations have been suggested:2,4,5
The drops should be used for the shortest duration possible.
Instruct the patient precisely regarding the dosage and duration of therapy.
Have the patient apply the drops onto a carrier medium such as a gauze strip.
Advise the patient to stop the treatment as soon as the discharge subsides.
Advise the patient to stop the treatment if hearing loss, tinnitus, vertigo
or imbalance is noted.
Reassess the need for ear drops 5-7 days after the start of treatment.
For patients with tympanic membrane defects, the risks of using
aminoglycoside otic preparations should be weighed carefully against the benefits.
This article is under the responsibility of: Amal Hélal,
BSc Phm, Bureau of Drug Surveillance
Références
1.Dukes M, editor. Meyler's side effects of drugs.
12th ed. Amsterdam: Elsevier; 1992.
2.Linder TE, Zwicky S, Brandle PB. Ototoxicity of ear drops:
a clinical perspective. Am J Otology 1995;16:653-7.
3.Welling DB, Forrest LA, Goll F III. Safety of ototopical
antibiotics. Laryngoscope 1995;105:472-4.
4.Rutka JA, Wong DLH. Do aminoglycoside otic preparations
cause ototoxicity in the presence of tympanic membrane perforations? Otolaryngol
Head Neck Surg 1997. In press.
5.Longridge DB. Topical gentamycin vestibular toxicity. J Otolaryngol
1994;23:444-6.
Spontaneous reporting of suspected adverse drug reactions (ADRs)
is a critical ongoing source of drug-safety information. Thus, we encourage
health professionals to report any suspected ADRs to one of the following addresses:
British Columbia
BC Regional ADR Centre
c/o BC Drug and Poison Information Centre
1081 Burrard St.
Vancouver BC V6Z 1Y6
fax: 604 631-5262; tel: 604 631-5625
adr@dpic.bc.ca
Saskatchewan
Sask ADR Regional Centre
Dial Access Drug Information Service
College of Pharmacy and Nutrition
University of Saskatchewan
Saskatoon SK S7N 5C9
fax:306 966-6377;tel:306 966-6340 or 800 667-3425
vogt@duke.usask.ca
Quebec
Quebec Regional ADR Centre
Centre d'information pharmaceutique
Hôpital du Sacré Coeur de Montréal
5400, boul. Gouin ouest
Montréal QC H4J lC5
fax: 514 338-3670; tel: 514 338-2961 or
338-2161 (collect calls accepted)
cip.hscm@sympatico.ca
Nova Scotia, New Brunswick,
Newfoundland and Prince Edward Island
Atlantic Regional ADR Centre
Queen Elizabeth II Health Sciences Centre
New Halifax Infirmary Building
Level 200, Drug Information Centre
1796 Summer St.
Halifax NS B3H 3A7
fax: 902 473-8612; tel: 902 473-7171
rxkls1@qe2-hsc.ns.ca
Other provinces and the territories
Adverse Drug Reaction Reporting Unit
Continuing Assessment Division
Bureau of Drug Surveillance
Drugs Directorate
AL 4103B1
Ottawa ON K1A 1B9
fax 613 957-0335; tel 613 957-0337
cadrmp@hc-sc.gc.ca
Please Note: A voluntary reporting system thrives on
intuition, lateral thinking and openmindedness. Eor these reasons, most adverse
drug reactions (ADRs) can be considered only to be suspicions, for which a proven
causal association has not been established. Because there is qross underreporting
of ADRs and because a definite causal association cannot be determined, this
information cannot be used to estimate the incidence of adverse reactions.
ADRs are nevertheless invaluable as a source of potential
new and undocumented signals.
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